Osteoporosis is an important disease of aging. The health and economic burdens imposed by this disease are enormous. Incapacitating pain, loss of height and consequences of osteoporotic fracture are often devastating, resulting in loss of independent function or even death. As the population ages efforts to prevent osteoporotic fractures by non-pharmacological and pharmacological means are of utmost importance. Considerable attention has focused recently on understanding the cellular mechanisms by which bone loss occurs in osteoporosis. Evidence indicates that parathyroid hormone (PTH) has an important role in mediating this phenomenon. PTH causes loss of skeletal mineral by stimulating production of pro-resorptive cytokines either systemically or locally in the bone microenvironment. Work from our laboratory has suggested a critical role for interleukin-6 (IL-6) in mediating the resorptive effects of PTH in vivo. The focus of our research has been on PTH-dependent regulation of IL-6 and IL-6 soluble receptor expression and the role of the PTH-IL-6 axis in the pathogenesis of osteoporosis. A series of animal and human studies completed by our group indicate, in aggregate, that IL-6 is a required down-stream mediator of bone resorption induced by PTH in states of enhanced PTH activity. We hypothesize that IL-6 is an important mediator of PTH's resorptive actions in bone and that in the estrogen-deficient state, PTH dependent IL-6 production is exaggerated. To date our data support the hypothesis that the increased skeletal sensitivity to PTH in the estrogen-deficient state is mediated by augmented PTH-induced IL-6 production. To continue to study this hypothesis we will: 1. Examine the newly formed hypothesis that racial differences in the resorptive response to PTH infusion in postmenopausal women, are due to differential PTH-induced increases in the production of pro-resorptive cytokines. We will also continue our studies as previously proposed in K08 Award (K08 DK02596) to: 2. Determine whether neutralizing IL-6 in vivo blocks PTH-induced bone loss in mice and whether IL-6 knock-out mice do not lose bone in response to PTH. We will also explore the effect of ovariectomy on PTH-induced bone resorption in wild type and knock-out mice. 3. Examine the molecular mechanism underlying PTH-induced increases in IL-6 production by bone cells and the modulating effect of estrogen on this process.